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Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B

Activation of toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) Unfolded Protein Response (UPR) to accommodate essential protein translation(1,2). However, despite increased p-eIF2α, a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis, and translationa...

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Autores principales: Woo, Connie W., Kutzler, Lydia, Kimball, Scot R., Tabas, Ira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271190/
https://www.ncbi.nlm.nih.gov/pubmed/22231169
http://dx.doi.org/10.1038/ncb2408
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author Woo, Connie W.
Kutzler, Lydia
Kimball, Scot R.
Tabas, Ira
author_facet Woo, Connie W.
Kutzler, Lydia
Kimball, Scot R.
Tabas, Ira
author_sort Woo, Connie W.
collection PubMed
description Activation of toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) Unfolded Protein Response (UPR) to accommodate essential protein translation(1,2). However, despite increased p-eIF2α, a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis, and translational suppression of critical proteins(3). Because p-eIF2α decreases the functional interaction of eIF2 with eIF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signaling activates eIF2B-GEF activity to counteract the effects of p-eIF2α. We now show that TLR-TRIF signaling activates eIF2B-GEF through PP2A-mediated Ser-dephosphorylation of the eIF2B ε-subunit. PP2A itself is activated by decreased Src-family-kinase-induced Tyr-phosphorylation of its catalytic subunit. Each of these processes are required for TLR-TRIF-mediated CHOP suppression in ER-stressed cells in vitro and in vivo. Thus, in the setting of prolonged, physiologic ER stress, a unique TLR-TRIF-dependent translational control pathway enables cells to carry out essential protein synthesis and avoid CHOP-induced apoptosis while still benefitting from the protective arms of the UPR.
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spelling pubmed-32711902012-08-01 Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B Woo, Connie W. Kutzler, Lydia Kimball, Scot R. Tabas, Ira Nat Cell Biol Article Activation of toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) Unfolded Protein Response (UPR) to accommodate essential protein translation(1,2). However, despite increased p-eIF2α, a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis, and translational suppression of critical proteins(3). Because p-eIF2α decreases the functional interaction of eIF2 with eIF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signaling activates eIF2B-GEF activity to counteract the effects of p-eIF2α. We now show that TLR-TRIF signaling activates eIF2B-GEF through PP2A-mediated Ser-dephosphorylation of the eIF2B ε-subunit. PP2A itself is activated by decreased Src-family-kinase-induced Tyr-phosphorylation of its catalytic subunit. Each of these processes are required for TLR-TRIF-mediated CHOP suppression in ER-stressed cells in vitro and in vivo. Thus, in the setting of prolonged, physiologic ER stress, a unique TLR-TRIF-dependent translational control pathway enables cells to carry out essential protein synthesis and avoid CHOP-induced apoptosis while still benefitting from the protective arms of the UPR. 2012-01-08 /pmc/articles/PMC3271190/ /pubmed/22231169 http://dx.doi.org/10.1038/ncb2408 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Woo, Connie W.
Kutzler, Lydia
Kimball, Scot R.
Tabas, Ira
Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B
title Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B
title_full Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B
title_fullStr Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B
title_full_unstemmed Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B
title_short Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP and translation inhibition through activation of eIF2B
title_sort toll-like receptor activation suppresses endoplasmic reticulum stress-induced chop and translation inhibition through activation of eif2b
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271190/
https://www.ncbi.nlm.nih.gov/pubmed/22231169
http://dx.doi.org/10.1038/ncb2408
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